Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor (FGF) family which acts on a variety of epithelial cell types, but is distinct from other known FGFs in that it is not mitogenic for fibroblasts or endothelial cells. We have found specific KGF binding to surface receptors on BALB/MK keratinocytes which was competed efficiently by acidic FGF, but with 100-fold lower efficiency by basic FGF. The pattern of binding and competition on BALB/MK and NIH/3T3 fibroblasts suggests that these cell types possess related but distinct FGF receptors. Scatchard analysis of KGF binding suggested two high affinity components and a third, high capacity/low affinity heparin-like component. Covalent affinity cross-linking of KGF to its receptor on BALB/MK cells also revealed two high affinity species. We have preliminarily characterized several early substrates of growth factor receptor tyrosine kinases. Some appear to be common to several different receptor pathways, e.g. , phospholipase C gamma (PLC-gamma) ; while others, such as the GTPase activating protein (GAP) of p2l ras, appear to be cell type- and/or ligand-specific. Both of these substrates directly link growth factor receptor signalling at the cell surface to diverse growth-related intracellular biochemical pathways. We have also identified a tyrosine-specific protein phosphatase from bovine liver, and characterized its activity on activated epidermal growth factor (EGF) receptor. The potential interaction of this phosphatase with FGF receptors is currently under investigation.